Genetic inhibition of CARD9 accelerates the development of atherosclerosis in mice through CD36 dependent-defective autophagy.
| Title: | Genetic inhibition of CARD9 accelerates the development of atherosclerosis in mice through CD36 dependent-defective autophagy. |
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| Authors: | Zhang Y; Université Paris Cité, INSERM U970, Paris Cardiovascular Research Center, Paris, France.; Vandestienne M; Université Paris Cité, INSERM U970, Paris Cardiovascular Research Center, Paris, France.; Lavillegrand JR; Université Paris Cité, INSERM U970, Paris Cardiovascular Research Center, Paris, France.; Joffre J; Université Paris Cité, INSERM U970, Paris Cardiovascular Research Center, Paris, France.; Sorbonne Université, Paris, France.; Santos-Zas I; Université Paris Cité, INSERM U970, Paris Cardiovascular Research Center, Paris, France.; Lavelle A; Sorbonne Université, Paris, France.; Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, CRSA, AP-HP, Saint Antoine Hospital, Gastroenterology department, Paris, France.; Zhong X; Université Paris Cité, INSERM U970, Paris Cardiovascular Research Center, Paris, France.; Le Goff W; Inserm UMRS1166, ICAN, Institute of CardioMetabolism and Nutrition, Hôpital Pitié-Salpêtrière (AP-HP), Paris, France.; Guérin M; Inserm UMRS1166, ICAN, Institute of CardioMetabolism and Nutrition, Hôpital Pitié-Salpêtrière (AP-HP), Paris, France.; Al-Rifai R; Université Paris Cité, INSERM U970, Paris Cardiovascular Research Center, Paris, France.; Laurans L; Université Paris Cité, INSERM U970, Paris Cardiovascular Research Center, Paris, France.; Bruneval P; Université Paris Cité, INSERM U970, Paris Cardiovascular Research Center, Paris, France.; Department of Anatomopathology, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.; Guérin C; Institut Curie, Cytometry Platform, 75006, Paris, France.; Diedisheim M; Clinique Saint Gatien Alliance (NCT+), 37540 Saint-Cyr-sur-Loire, France; Institut Necker-Enfants Malades (INEM), Université Paris Cité, INSERM UMR-S1151, CNRS UMR-S8253, 75015, Paris, France.; Migaud M; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Imagine Institute, 75015, Paris, France.; Puel A; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Imagine Institute, 75015, Paris, France.; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA.; Lanternier F; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Imagine Institute, 75015, Paris, France.; Casanova JL; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Imagine Institute, 75015, Paris, France.; Cochain C; Comprehensive Heart Failure Center Wuerzburg, University Hospital Wuerzburg, Wuerzburg, Germany.; Institute of Experimental Biomedicine, University Hospital Wuerzburg, Wuerzburg, Germany.; Zernecke A; Institute of Experimental Biomedicine, University Hospital Wuerzburg, Wuerzburg, Germany.; Saliba AE; Helmholtz Institute for RNA-based Infection Research (HIRI), Helmholtz-Center for Infection Research (HZI), Wuerzburg, Germany.; Mokry M; Laboratory of Experimental Cardiology, Department of Cardiology, University Medical Center Utrecht, University Utrecht, Utrecht, Netherlands.; Silvestre JS; Université Paris Cité, INSERM U970, Paris Cardiovascular Research Center, Paris, France.; Tedgui A; Université Paris Cité, INSERM U970, Paris Cardiovascular Research Center, Paris, France.; Mallat Z; Université Paris Cité, INSERM U970, Paris Cardiovascular Research Center, Paris, France.; Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, CB2 2QQ, UK.; Taleb S; Université Paris Cité, INSERM U970, Paris Cardiovascular Research Center, Paris, France.; Lenoir O; Université Paris Cité, INSERM U970, Paris Cardiovascular Research Center, Paris, France.; Vindis C; CIC 1436/CARDIOMET, Inserm, 1048, Toulouse, France.; Camus SM; Université Paris Cité, INSERM U970, Paris Cardiovascular Research Center, Paris, France.; Sokol H; Sorbonne Université, Paris, France.; Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, CRSA, AP-HP, Saint Antoine Hospital, Gastroenterology department, Paris, France.; University Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, Jouy-en-Josas, France.; Paris Center for Microbiome Medicine (PaCeMM) FHU, Paris, France.; Ait-Oufella H; Université Paris Cité, INSERM U970, Paris Cardiovascular Research Center, Paris, France. hafid.aitoufella@inserm.fr.; Sorbonne Université, Paris, France. hafid.aitoufella@inserm.fr.; Medical Intensive Care Unit, Hôpital Saint-Antoine, AP-HP, Sorbonne Université, Paris, France. hafid.aitoufella@inserm.fr. |
| Source: | Nature communications [Nat Commun] 2023 Aug 01; Vol. 14 (1), pp. 4622. Date of Electronic Publication: 2023 Aug 01. |
| Publication Type: | Journal Article; Research Support, Non-U.S. Gov't |
| Language: | English |
| Journal Info: | Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: [London] : Nature Pub. Group |
| MeSH Terms: | Atherosclerosis*/metabolism; Autophagy/genetics ; CARD Signaling Adaptor Proteins/metabolism ; Apolipoproteins E/genetics ; Mice, Knockout ; Humans ; Mice ; Mice, Inbred C57BL ; Lipids ; Candidiasis, Chronic Mucocutaneous ; Animals |
| Abstract: | Caspase recruitment-domain containing protein 9 (CARD9) is a key signaling pathway in macrophages but its role in atherosclerosis is still poorly understood. Global deletion of Card9 in Apoe-/- mice as well as hematopoietic deletion in Ldlr-/- mice increases atherosclerosis. The acceleration of atherosclerosis is also observed in Apoe-/-Rag2-/-Card9-/- mice, ruling out a role for the adaptive immune system in the vascular phenotype of Card9 deficient mice. Card9 deficiency alters macrophage phenotype through CD36 overexpression with increased IL-1β production, increased lipid uptake, higher cell death susceptibility and defective autophagy. Rapamycin or metformin, two autophagy inducers, abolish intracellular lipid overload, restore macrophage survival and autophagy flux in vitro and finally abolish the pro-atherogenic effects of Card9 deficiency in vivo. Transcriptomic analysis of human CARD9-deficient monocytes confirms the pathogenic signature identified in murine models. In summary, CARD9 is a key protective pathway in atherosclerosis, modulating macrophage CD36-dependent inflammatory responses, lipid uptake and autophagy.; (© 2023. The Author(s).) |
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| Grant Information: | CH/10/001/27642 United Kingdom BHF_ British Heart Foundation; R01 AI127564 United States AI NIAID NIH HHS |
| Substance Nomenclature: | 0 (Apolipoproteins E); 0 (Lipids); 0 (CARD Signaling Adaptor Proteins); 0 (CARD9 protein, human); 0 (Card9 protein, mouse) |
| SCR Disease Name: | Candidiasis familial chronic mucocutaneous, autosomal recessive |
| Entry Date(s): | Date Created: 20230801 Date Completed: 20230803 Latest Revision: 20250530 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC10394049 |
| DOI: | 10.1038/s41467-023-40216-x |
| PMID: | 37528097 |
| Database: | MEDLINE |
Journal Article; Research Support, Non-U.S. Gov't